Proprotein convertase subtilisin/kexin type 9 (PCSK9) has recently become recognized as a key player in regulating cholesterol metabolism and has emerged as a promising target for prevention and treatment of coronary heart disease (CHD) (see, e.g., Seidah et al., Proc. Natl. Acad. Sci. U.S.A 100:928-33, 2003). Gain-of-function (GOF) mutations in PCSK9 have been found to be associated with autosomal dominant hypercholesterolaemia (ADH) (see, e.g., Abifadel et al., Nat. Genet. 34:154-6, 2003), mild to severe hypercholesterolaemia, and an increased risk of CHD (see, e.g., Davignon et al., Curr. Atheroscler. Rep. 12:308-15, 2010). Conversely, the loss-of-function (LOF) mutations in PCSK9 are associated with lifelong reductions in low-density lipoprotein cholesterol (LDL-C) (see, e.g., Cohen et al., Nat. Genet. 37:161-5, 2005; and Tibolla et al., Nutr. Metab. Cardiovasc. Dis. 21:835-43, 2011). Further, the LOF mutations in PCSK9 have been found to reduce the atherosclerosis and CHD risk (see, e.g., Cohen et al., N Eng J Med 354: 1264-72, 2010; Benn et al., J Am Coll Cardiol 55:2833-42, 2010); whereas the complete loss of PCSK9 results in low serum LDL-C of <20 mg/dl in human health subjects (Hooper et al., Atheroscler. 193:445-8, 2007; and Zhao et al., Am. J. Hum. Genet. 79: 514-23, 2006).
The main way by which PCSK9 regulates LDL-C levels is modulating the degradation of the LDL receptor (LDLR) by direct interaction with the LDLR both within the cell and at the surface of the plasma membrane (see, e.g., Seidah et al., Nat. Rev. Drug. Discov. 11:367-83, 2012; and Lambert et al., J. Lipid. Res. 53:2515-24, 2012). Highly expressed in the liver and intestine, PCSK9 is secreted after the autocatalytic cleavage of the prodomain and can bind to the LDLR in a complex, which triggers modification of LDLR conformation, avoiding the normal recycling of LDLR to the plasma membrane, and increasing LDLR lysosomal degradation (see e.g., Horton et al, J. Lipid. Res. 50:S172-S177, 2009; Piper et al., Structure 15:545-52, 2007; and Lo Surdo et al., EMBO Rep. 12:1300-5, 2011).
Various therapeutic approaches for inhibiting PCSK9 are currently in development, including gene silencing by siRNA or anti-sense oligonucleotides and disruption of the PCSK9-LDLR interaction by antibodies. Brautbar et al., Nature Reviews Cardiology 8, 253-265, 2011. Further, various PCSK9 antagonist antibodies have also been reported for the treatment of serum cholesterol reduction as well as primary and secondary atherosclerotic cardiovascular disease (ASCVD). See, e.g., U.S. Pat. Nos. 8,080,243, 8,030,457, 8,062,640, and US20140161821.
While the lower levels of LDL-C achievable with currently available lipid-lowering therapies do not appear to be harmful (see, e.g., LaRosa et al., Am. J. Cardiol. 111:1221-1229, 2013), the safety of very low levels of LDL-C achievable with PCSK9 inhibitors, particularly when sustained over a prolonged period, is unclear (see LaRosa, supra., and Dadu et al., Nat. Rev. Cardiol. Doi:10.1038/nrcardio.2014.84, 2014). Previous epidemiological studies and data from earlier statin trials suggested an association between lower levels of LDL-C and increased risk of cancer, hemorrhagic stroke, and non-cardiac death: an association that has not been supported by subsequent outcome studies and large meta-analyses (see, e.g., La Rosa et al., supra; and Dadu et al., supra). Concerns have also been raised regarding possible cognitive symptoms associated with very low LDL-C levels. (See, e.g., Dadu et al., supra). Accordingly, it remains unclear what are the lower doses of PCSK9 antagonist antibody that would still be considered effective and efficacious to treat LDL-C related disorders in patients while preventing extremely low levels of LDL-C.